Generally, intimal thickening involving inter alia PDGF-triggered smooth muscle cell proliferation and migration is a major complication after surgical, catheter or endoscopic treatment of blood vessels, like treatment of atherosclerosis by angioplasty, stenting or bypass grafting.
For example, restenosis is a frequent complication after percutaneous transluminal coronary angioplasty (PTCA), leading to obstruction in about 20 to 30% of patients within 6 months after the procedure. A key element in the pathogenesis is damage to the endothelium. Dysfunctional or absent endothelium in addition predisposes arteries for various other pathological conditions, inter alia leading to thrombosis and spasm.
Intimal thickening has been described as a response-to-injury phenomenon. Disruption of the protective endothelial cell layer appears to trigger subsequent stimulation of migration and proliferation of smooth muscle cells, partly mediated by PDGF receptor stimulation, which ultimately leads to formation of a neointima composed predominantly of smooth muscle cells and extracellular matrix components. Inhibition of smooth muscle cell proliferation through the use of PDGF antagonists or restoration of the protective endothelial cell layer thus appeared as possible strategies for interference.
Limited beneficial effects have been observed by local treatment with members of the VEGF family, which were demonstrated to increase re-endothelialization and reduce intimal hyperplasia. Similarly, certain effects were observed with various types of PDGF antagonists including PDGF neutralizing antibodies, PDGF receptor antibodies, PDGF aptamers and low-molecular weight tyrosine kinase inhibitors.
For example, gene transfer to the vessel wall was described to provide a new possibility for the treatment of such vascular disorders, especially postangioplasty restenosis. The positive effect of adenovirus-mediated vascular endothelial growth factor (VEGF)-C transfer on neointima formation after endothelial denudation in rabbits has been examined (see M. O. Hiltunen et al., Circulation 102, p. 2262-8 (2000)). Rabbits with balloon-denuded aortas were subjected to gene transfer 3 days after denudation. After 2 and 4 weeks, the intima/media ratio (I/M), histology and cell proliferation were analyzed. 2 weeks after gene transfer, in a control lacZ-transfected control group the I/M ratio was showed a mean value of 0.57, while VEGF-C gene transfer reduced the I/M to a mean value of 0.38 (p<0.05 versus lacZ group). Also after 4 weeks, the I/M value for the VEGF-C group was below that for the lacZ-group. It was concluded that VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations. However, the durability of the effect turned out to be questionable (see T. Asahara et al., Circulation 91, 2793-801 (1995) and M. O. Hiltunen et al., Circulation 102, 2262-8 (2000).
On the other hand, a mouse/human chimeric anti-platelet-derived growth factor-β receptor antibody in combination with heparin has been shown to inhibit intimal hyperplasia in the saphenous artery of the baboon after balloon angioplasty (see C. E. Hart et al., Circulation 99, 564-9 (1999)). These data suggested that platelet-derived growth factor plays a key role in the development of intimal lesions at sites of acute vascular injury in the nonhuman primate. Also, the orally active PDGF-receptor tyrosine kinase inhibitor RPR101511A (6,7-di-methoxy-2-thiophen-3-yl-quinoxaline hydrochloride) was shown to inhibit the cell-free and in situ PDGF-receptor tyrosine kinase and PDGF-receptor dependent proliferation and chemotaxis in vascular smooth muscle cells. PTCA in hypercholesterolemic minipigs whose left anterior descending coronary artery had been injured by overdilatation and denudation, yielding a predetermined lesion. In contrast to controls without RPR101511A, the gain in diameter remained in RPR101511A-treated minipigs, and morphometric analysis showed that RPR101511A caused a significant decrease in total intima/media ratio. It was concluded that the PDGF-receptor tyrosine kinase inhibitor RPR101511A prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia. In addition, STI571 (N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine as methane sulfonate salt), a low molecular weight inhibitor of PDGF receptor tyrosine kinase, has been described to inhibit smooth muscle proliferation and leasion formation after re-injury of the arterial intima (Myllärniemi et al., Cardiovasc. Drugs and Ther. 13, 159-168 (1999)).
Antagonists of PDGF have, on the other hand, been demonstrated to show beneficial effects in animal restenosis models, but lesion recurrence has been observed after PDGF antagonist withdrawal (see O. Leppänen et al., Arterioscler. Thromb. Vasc. Biol. 20, E89-E95 (2000)).
These findings suggest a need to look for a combination of targeting smooth muscle cells treatment with other strategies.